ABSTRACT Support is requested for a Keystone Symposia conference entitled Phenotypic Drug Discovery: Recent Advances and Insights from Chemical and Systems Biology, organized by Drs. Mark Mercola, Fabien Vincent, Monica Schenone and Arsenio Nueda. The conference will be held in Breckenridge, Colorado from March 3-7, 2019. Unlike conventional target-centric drug discovery, Phenotypic Drug Discovery (PDD) places its focus on disease- relevant phenotypes and agnosticism with regard to molecular mechanism of action. Thus, it offers unique opportunities in terms of discovery of novel biology and first-in-class therapeutics but is matched with significant challenges, a number of which can be addressed by recent advances in chemical and systems biology. A key aspect of the conference will be to share information and processes on how best to employ phenotypic strategies to discover novel biology and effectively prosecute drug discovery programs. Specific topics will include: chemical biology advances and case studies in target identification; case studies of recently advanced clinical candidates and approved drugs; functional genomics and systems biology advances and case studies; project prosecution including lessons learned from lead optimization and pre-clinical development; complex cell-based models and new assay modalities. With few non-commercial meetings covering drug discovery as a discipline, this conference has the stature and breadth to bring together accomplished and influential scientists from industry and academia as demonstrated by the 2016 conference. Its scope will be broader than other PDD and Chemical Biology meetings since it will cover the entire range of activities and technologies from phenotypic assay systems, to target identification and FDA approval of novel therapeutics. Given that there is still an emphasis on target centric discovery in pharmaceutical companies, this conference can be instrumental in further promoting a shift in mindset and contributing to the consolidation of PDD as an integral part of the drug discovery paradigm. The vision for this conference would be to share success stories of newly approved drugs and late stage clinical candidates, along with key lessons and best practices, to inform future PDD projects.